Isolated growth hormone (GH) deficiency due to compound heterozygosity fortwo new mutations in the GH-releasing hormone receptor gene

OBJECTIVE Mutations in the GH releasing hormone receptor (GHRH-R) have rece ntly been shown to cause autosomal recessive isolated GH deficiency (IGHD). Patients who are homozygous for GHRH-R mutations have a subnormal GH respo nse to pharmacological agents that stimulate GH secretion and an appropriat e response to exogenous GH therapy. We searched for mutations in the GHRH-R gene in a family in which two of three siblings were affected by IGHD. DESIGN We sequenced the 13 coding exons, the intron-exon boundaries and 327 bases of the promoter of the GHRH-R gene from peripheral blood cell genomi c DNA of an index patient. RESULTS Both affected individuals were compound heterozygotes for two previ ously undescribed GHRH-R mutations: a change in codon 137 that replaces his tidine with leucine (H137L), and a 5 bp deletion in exon 11 (Del 1140-1144) . The patients' father was heterozygous for the H137L mutation, and the mot her was heterozygous for the exon 11 deletion. We used site-directed mutage nesis to create the mutants in wild-type GHRH-R cDNA. Transient transfectio n of GHRH-R cDNAs in Chinese hamster ovary cells showed that cells transfec ted with both mutant receptors failed to increase cyclic AMP after treatmen t with GHRH. CONCLUSIONS We describe a family in which two siblings with IGHD were compo und heterozygotes for two new mutations in the GHRH-R gene. These results s uggest that mutant alleles for GHRH-R gene may be more common than previous ly suspected.